The invention pertains to novel substituted spirocyclopropyl fluorenes having drug and bio-affecting properties and to their preparation, pharmaceutical formulations and use. In particular, the invention concerns spirocyclopropylfluorenes having aminomethyl, methoxy and other substituents. These compounds possess melatonergic properties that should make them useful in treating certain medical disorders.
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone which is synthesized and secreted primarily by the pineal gland. Melatonin levels show a cyclical, circadian pattern with highest levels occurring during the dark period of a circadian light-dark cycle. Melatonin is involved in the transduction of photoperiodic information and appears to modulate a variety of neural and endocrine functions in vertebrates, including the regulation of reproduction, body weight and metabolism in photoperiodic mammals, the control of circadian rhythms and the modulation of retinal physiology.
Recent evidence demonstrates that melatonin exerts its biological effects through specific receptors. Use of the biologically active, radiolabelled agonist [.sup.125 I]-2-iodomelatonin has led to the identification of high affinity melatonin receptors in the CNS of a variety of species. The sequences of two cloned human melatonin receptors have been reported [Reppert, et al., Proc. Nat. Acad. Sci. 92: 8734-8738 (1995) and Reppert, et al., Neuron 13: 1177-1185 (1994)]. In mammalian brain, autoradiographic studies have localized the distribution of melatonin receptors to a few specific structures. Although there are significant differences in melatonin receptor distribution even between closely related species, in general the highest binding site density occurs in discreet nuclei of the hypothalamus. In humans, specific [.sup.125 I]-2-iodomelatonin binding within the hypothalamus is completely localized to the suprachiasmatic nucleus, strongly suggesting the melatonin receptors are located within the human biological clock.
Exogenous melatonin administration has been found to synchronize circadian rhythms in rats (Cassone, et al., J. Biol. Rhythms, 1:219-229, 1986). In humans, administration of melatonin has been used to treat jet-lag related sleep disturbances, considered to be caused by desynchronization of circadian rhythms (Arendt, et al., Br. Med. J. 292:1170, 1986). Further, the use of a single dose of melatonin to induce sleep in humans has been claimed by Wurtman in International Patent Application WO 94/07487. Thus, melatonin agonists should be particularly useful for the treatment of sleep disorders and other chronobiological disorders. Melatonin agonists would also be useful for the further study of melatonin receptor interactions as well as in the treatment of conditions affected by melatonin activity, such as depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproduction, cancer, benign prostatic hyperplasia, premenstrual syndrome, inflammatory articular diseases, immune disorders, and neuroendorine disorders.
Aside from simple indole derivatives of melatonin itself, various bicyclic structures have been prepared and their use as melatonin ligands disclosed. In general these bicyclic amide structures can be represented as: ##STR2## wherein Z is an aryl or heteroaryl system attached by a two carbon bridge to the amide group. Some specific examples follow.
Yous, et al. in European Patent Application EP-527,687A disclose as melatonin ligands arylethylamines i, ##STR3## wherein Ar' is, inter alia, a substituted or unsubstituted benzo[b]thiophen-3-yl, benzimidazol-1-yl, benzo[b]furan-3-yl, 1,2-benzisoxazol-3-yl, 1,2-benzisothiazol-3-yl, or indazol-3-yl radical; R.sub.1 is, inter alia, an alkyl or cycloalkyl group; and R.sub.2 is hydrogen or lower alkyl.
Yous, et al. in European Patent Application EP-506,539A claim melatonin ligands ii, ##STR4## wherein A is oxygen or sulfur; X is a methylene group or a bond; and R is H or lower alkyl when p is 1 and B is defined by the radical iii, ##STR5## wherein R.sub.1 is hydrogen or lower alkyl and R.sub.2 is, inter alia, hydrogen, lower alkyl or cycloalkyl. Alternatively, R is defined by the radical iii when p is 0 or 1 and B is lower alkoxy.
Several naphthalene derivatives have also been disclosed as melatonin ligands.
Andrieux, et al. in European Patent Application EP-447,285A claim amidoalkylnaphthalenes iv, ##STR6## wherein R is lower alkyl; R.sub.1 is hydrogen or lower alkyl; and R.sub.2 is, inter alia, hydrogen, lower alkyl, or cycloalkyl.
Yous, et al. in European Patent Application EP-562,956A disclose amide and urea naphthalene derivatives v, ##STR7## in which R is hydrogen or OR.sub.4 wherein R.sub.4 is, inter alia, hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl; R.sub.1 is hydrogen or COOR.sub.5 wherein R.sub.5 is hydrogen or alkyl; R.sub.2 is hydrogen or alkyl; X is NH or a bond; and R.sub.3 is, inter alia, alkyl, alkenyl, or cycloalkyl.
Lesieur, et al. in European Patent Application EP-530,087A disclose naphthylethylureas and naphthylethylthioureas vi, ##STR8## in which R is hydrogen or OR.sub.3 wherein R.sub.3 is, inter alia, hydrogen, lower alkyl, or cycloalkyl; R.sub.1 is hydrogen or lower alkyl; X is oxygen or sulfur; and R.sub.2 is, inter alia, lower alkyl or cycloalkyl.
Langlois, et al., in Australian Patent Application AU-A-48729/93 disclose arylalkyl(thio)amides vii as melatonergic ligands, ##STR9## wherein R.sub.1 is hydrogen or lower alkyl; R.sub.2 is hydrogen, halogen, or lower alkyl; R.sub.3 and R.sub.4 are identical or different groups including, inter alia, hydrogen, halogen, or lower alkyl or R.sub.3 and R.sub.4, together with the benzene ring which carries them, form a ring-system E.sub.3 chosen from, inter alia, naphthalene, on the understanding that the portion of the ring-system E.sub.3 formed by R.sub.3 and R.sub.4 and the two carbon atoms of the benzene ring which carry them is unhydrogenated or partially hydrogenated; R.sub.5 is hydrogen or lower alkyl; and R.sub.6 is, ##STR10## wherein X is sulfur or oxygen and R.sub.7 is, inter alia, lower alkyl or alkenyl.
Horn and Dubocovich in European Patent Application EP-420,064A disclose 2-amidotetralins viii as melatonin ligands, ##STR11## wherein R.sub.1 is, inter alia, hydrogen, lower alkyl, or lower alkoxyl; R.sub.2 is, inter alia, hydrogen, halogen, or lower alkoxyl; R.sub.3 is, inter alia, hydrogen, or lower alkyl; R.sub.4 is, inter alia, lower alkyl, haloalkyl or cycloalkyl; and R.sub.5 is hydrogen, hydroxyl, halogen, oxo, aryl, lower alkyl or alkylaryl.
Copinga et al, in J. Med. Chem., 1993, 36, p. 2891, discusses amidomethoxytetralins of structure ix and their melatonergic properties. ##STR12##
In structure ix, R.sub.1 is H or OCH.sub.3 and R.sub.2 is alkyl, haloalkyl, phenylalkyl or phenyl.
U.S. Pat. No. 3,419,604 discloses antidepressant compounds of structure x: ##STR13## wherein n=0-2, and R.sup.1 and R.sup.2 are hydrogen, lower alkyl or are taken together in a cyclic amino group.
U.S. Pat. No. 5,596,019 and European Patent EP-747,346 A2 disclose, respectively, N-acyl-cycloalkylamine derivatives and N-acyl-2-aryl cyclopropylmethylamine derivatives which are useful as melatonergic agents.
The foregoing disclosures do not teach or suggest the novel melatonergic spirocyclopropylfluorenes of the present invention. The novel compounds of the present invention are melatonergic agonists with good affinity for human melatonin receptors which should make them useful for treating disorders associated with the melatonergic system.